The accumulation of heritable genetic and epigenetic changes that result in loss of function of tumor suppressors and/or inappropriate activation of proto-oncogenes is a hallmark of cancer. The goals of the Molecular Genetics and Epigenetics Program (GEN) are to understand the molecular mechanisms that underlie these defects and to uncover new targets for therapy, diagnosis, prognosis, and prevention. The Program capitalizes on the large number of outstanding investigators at UVA with research expertise in chromatin architecture, transcription, replication. mutation, repair, and cellular checkpoints in cancer. The Members are organized around four main themes: (1) Chromosome function, malfunction, and cellular checkpoints; (2) Epigenetics and cancer; (3) Signaling and gene expression in cancer; and (4) Bioinformatics: mining information from human genomes. The Program is led by Joyce L. Hamlin, PhD, an expert in mammalian DNA replication and large-scale chromosome rearrangements in tumor cells; and by Anindya Dutta, MD, PhD a leader in the replication and cell cycle fields. Dr. Dutta has focused more recently on the role of microRNAs in tumorigenesis. Through its activities. GEN provides a formal mechanism for fostering intellectual exchange and collaboration among its Members. The Program currently consists of 32 Full Members and 6 Associate Members from 11 different departments. Twenty one of these individuals are new to the Program or to UVA since the last renewal, and they bring considerable expertise in the bioinformatics of microarray and deep-sequencing data, large-scale genomic rearrangements (including aneuploidy). and the molecular effects of radiation and cellular responses to radiation. Importantly for this renewal, GEN has added a significant cohort of translational and clinical investigators whose research focus is on particular tumor types, including lung and brain tumors, or on radiation damage. Total extramural funding for the Program exceeds $14.8 million, including $3.4 million from the National Cancer Institute (NCI) and an award from the American Cancer Society. Program Members have produced 390 cancer-relevant publications, of which 32% were inter-programmatic and 18% were intra-programmatic since the last renewal. In addition. Program Members participate in multi-investigator and collaborative National Institutes of Health research awards, including 18 grants from NCI.